Regulation of Energy Expenditure by NF-kB. NF-kB is a transcription factor that is activated in adipose tissue in obesity. NF-kB induces cytokine expression and inhibits lipid accumulation in adipocytes, which contribute to the pathogenesis of insulin resistance according to data derived from cellular models. To test the NF-kB activity in vivo, we enhanced and decreased NF-kB activity by overexpressing and knocking out of the p65 subunit. Fat-selective NF-kB activation induced a low grade inflammatory response in the fat tissue, and inhibited adiposity in the aP2-p65 mice. However, the inflammation did not impair systemic insulin sensitivity in the mice on either chow or high fat diet. The mice exhibited an increase in energy expenditure at room temperature and an elevation in thermogenesis in the cold environment. In fat-selective p65-KO mice, the thermogenesis was significantly impaired in the cold response leading to hypothermia in mice. The thermogenic alterations were associated with functional changes in brown adipose tissue (BAT) and white adipose tissues (WAT). The preliminary data suggests that NF-kB activation in adipose tissue may promote thermogenesis by enhancing BAT function and WAT browning. This possibility will be tested in three aims. The study will uncover the NF-kB activity in brown adipocytes and beige adipocytes for the first time. The results may provide answers to observations that the anti-inflammation therapies induce weight gain in humans, failure of anti-inflammatory therapy in insulin sensitization in most clinical trials, and disassociation of inflammation with insulin resistance in rodent models.